Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma

PurposeTo improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL.Patients and methodsChildren and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients.ResultsAALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS (P = .412) and OS (P = .600).ConclusionPatients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse

Cereals and pulse-based ready-to-use therapeutic food as an alternative to the standard milk- and peanut paste-based formulation for treating severe acute malnutrition: A noninferiority, individually randomized controlled efficacy clinical trial

Background: The cost of current standard ready-to-use therapeutic food (RUTF) is among the major obstacles to scaling up community- based management of acute malnutrition (CMAM), an important child survival strategy. Identifying a cheaper alternative is a global public health priority. Objective: We sought to compare the efficacy of soya-maizesorghum RUTF (SMS-RUTF) with that of standard peanut paste- based RUTF (P-RUTF). Design: We used a nonblinded, parallel-group, simple randomized controlled trial along with a day care approach that enrolled 2 groups of children aged 6-23 and 24-59 mo, respectively, with severe acute malnutrition (SAM). Results: Intention-to-treat (ITT) and per-protocol (PP) analyses showed noninferiority of SMS-RUTF compared with P-RUTF for the recovery rate [ITT: Δ =-2.0% (95% CI:-7.6%, 3.6%); PP:-1.9% (95% CI: -5.3%, 1.4%)], weight gain [Δ = -0.7 g · kg-1 · d-1 (95% CI: -1.3, 0.0 g · kg-1 · d-1)], and length of stay [D = 2.0 d (95% CI: -1.7, 5.8 d)] in children ·-4 mo of age. In children ≥23 mo of age, the recovery rate of SMS-RUTF was inferior to that of P-RUTF [ITT: Δ = -20.8% (95% CI: -29.9%, -11.7%); PP: -17.2% (95% CI: -25.6%, -8.7%)]. Treatment with SMS-RUTF resulted in a greater increase in hemoglobin [0.670 g/dL (95% CI: 0.420, 0.921 g/dL); P < 0.001]. Treatment with both RUTFs resulted in the replenishment of all of the amino acids tested except for methionine. There were no differences at discharge between RUTF groups in fat mass [Δ = 0.3 kg (95% CI: -0.6, 1.6 kg); P = 0.341] or fat mass index [Δ = 0.4 kg/m2 (95% CI: -0.3, 1.1 kg/m2); P = 0.262]. By contrast, comparisons of fat-free mass indicated lower concentrations than the community controls after treatment with either of the 2 RUTFs [Δ = -1.3 kg (95% CI: -2.4, -0.1 kg) and P = 0.034 for comparison between community controls and the SMS-RUTF group; Δ = -1.8 kg (95% CI: -2.9, -0.6 kg) and P = 0.003 for comparison between community controls and the P-RUTF group]. Conclusion: SMS-RUTF can be used to treat SAM in children aged ·24 mo to reduce the costs of CMAM programs. More research is required to optimize SMS-RUTF for younger children. This trial was registered in the Pan African Clinical Trial Registry as PACTR201303000475166.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis